Inhibitors of NF κ-B activity for treatment of diseases and disorders

Abstract

Peptides and methods of use thereof, are disclosed for use in treating various diseases and disorders, including inflammation, pain, oral mucositis, oral lesions, and cancer. The peptides modulate the activity of the transcription factor NF κB.

What is claimed is: 
     
       1. A peptide which inhibits the activity of NF κB selected from the group consisting of peptides of six amino acid residues in length, wherein the peptide comprises the sequence: 
       
         
           
                 
                 
               
                     
                   Xxx-Ala-Glu-Ala (CORE SEQUENCE (3)),  
                 
                     
                   or 
                 
                     
                     
                 
                     
                   Xxx-Ala-D-Glu-Ala (CORE SEQUENCE (4)),  
                 
             
                
                
                
                
               
            
           
         
         where Xxx is selected from the group consisting of Met, Ile, Val, Cys, Trp, Tyr, Phe, 5-methyl-Trp, β-styryl-Ala, diphenyl-Ala, α-aminobutyric acid, α-aminocaproic acid, norleucine, α-amino-2-phenylbutyric acid, α-Amino-1-naphthalenepropanoic acid, β-cyclohexyl-Ala, dehydroalanine, and β-tert-butyl-Ala; 
         with the proviso that peptides comprising the sequence LIAEAK (SEQ ID NO:009), peptides comprising the sequence LIANAK (SEQ ID NO:012), and peptides comprising SEQ ID NOS:041-113 are excluded. 
       
     
     
       2. The peptide of  claim 1 , wherein Xxx is selected from the group consisting of Met, Ile, Val, Cys, Trp, Tyr, and Phe. 
     
     
       3. The peptide of  claim 1 , wherein Xxx is selected from the group consisting of 5-methyl-Trp, β-styryl-Ala, diphenyl-Ala, α-aminobutyric acid, α-aminocaproic acid, norleucine, α-amino-2-phenylbutyric acid, α-Amino-1-naphthalenepropanoic acid, β-cyclohexyl-Ala, dehydroalanine, and β-tert-butyl-Ala. 
     
     
       4. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:003 (EIAEAL), SEQ ID NO:004 (SNVAEA), SEQ ID NO:005 (ANIAEA), SEQ ID NO:008 (LWAEAK), SEQ ID NO:011 (LVAEAH), SEQ ID NO:018 (Sar-Trp-Ala-Glu-Ala-NMeAl), SEQ ID NO:020 (AWAEAK), SEQ ID NO:030 (LVAEAK), SEQ ID NO:039 (SNVAEA), SEQ ID NO:019 (Sar-Trp-Ala-[D]Glu-Ala-Sar), or SEQ ID NO:021 (AWA[D]EAK). 
     
     
       5. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:003 (EIAEAL). 
     
     
       6. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:004 (SNVAEA). 
     
     
       7. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:005 (ANIAEA). 
     
     
       8. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:008 (LWAEAK). 
     
     
       9. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:011 (LVAEAH). 
     
     
       10. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:018 (Sar-Trp-Ala-Glu-Ala-NMeAl). 
     
     
       11. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:020 (AWAEAK). 
     
     
       12. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:030 (LVAEAK). 
     
     
       13. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:039 (SNVAEA). 
     
     
       14. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:019 (Sar-Trp-Ala-[ ]Glu-Ala-Sar). 
     
     
       15. The peptide of  claim 1 , wherein the peptide is a peptide of the sequence SEQ ID NO:021 (AWA[D]EAK). 
     
     
       16. A method of treating inflammation in a patient in need thereof, comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of one or more peptides of  claim 1  which inhibit the activity of NF kappa B. 
     
     
       17. The method of  claim 16 , wherein the one or more peptides are selected from the group consisting of peptides of
 CORE SEQUENCE (3): Xxx-Ala-Glu-Ala where Xxx is selected from the group consisting of Met, Ile, Val, Cys, Trp, Tyr, Phe, 5-methyl-Trp, allo-Ile, β-styryl-Ala, β-styryl-Ala, diphenyl-Ala, α-aminobutyric acid, α-aminocaproic acid, norleucine, α-amino-2-phenylbutyric acid, α-Amino-1-naphthalenepropanoic acid, β-cyclohexyl-Ala, dehydroalanine, and β-tert-butyl-Ala; 
 CORE SEQUENCE (4): Xxx-Ala-D-Glu-Ala where Xxx is selected from the group consisting of Met, Ile, Val, Cys, Trp, Tyr, Phe, 5-methyl-Trp, allo-Ile, β-styryl-Ala, β-styryl-Ala, diphenyl-Ala, α-aminobutyric acid, α-aminocaproic acid, norleucine, α-amino-2-phenylbutyric acid, α-Amino-1-naphthalenepropanoic acid, β-cyclohexyl-Ala, dehydroalanine, and β-tert-butyl-Ala; 
 and SEQ ID NO:003 (EIAEAL), SEQ ID NO:004 (SNVAEA), SEQ ID NO:005 (ANIAEA), SEQ ID NO:008 (LWAEAK), SEQ ID NO:011 (LVAEAH), SEQ ID NO:018 (Sar-Trp-Ala-Glu-Ala-NMeAl), SEQ ID NO:020 (AWAEAK), SEQ ID NO:030 (LVAEAK), SEQ ID NO:039 (SNVAEA), SEQ ID NO:019 (Sar-Trp-Ala-[D]Glu-Ala-Sar), and SEQ ID NO:021 (AWA[D]EAK). 
 
     
     
       18. The method of  claim 16 , wherein the one or more peptides are selected from the group consisting of peptides of CORE SEQUENCE (3), CORE SEQUENCE (3-N), CORE SEQUENCE (3-U), GROUP (3-S), GROUP (3-T), GROUP (3-V), GROUP (3-W), CORE SEQUENCE (4), CORE SEQUENCE (4-N), CORE SEQUENCE (4-U), GROUP (4-S), GROUP (4-T), GROUP (4-V), SEQ ID NO:003 (EIAEAL), SEQ ID NO:004 (SNVAEA), SEQ ID NO:005 (ANIAEA), SEQ ID NO:008 (LWAEAK), SEQ ID NO:011 (LVAEAH), SEQ ID NO:018 (Sar-Trp-Ala-Glu-Ala-NMeAl), SEQ ID NO:020 (AWAEAK), SEQ ID NO:030 (LVAEAK), SEQ ID NO:039 (SNVAEA), SEQ ID NO:019 (Sar-Trp-Ala-[D]Glu-Ala-Sar), and SEQ ID NO:021 (AWA[D]EAK). 
     
     
       19. The method of  claim 17 , wherein Xxx is Met. 
     
     
       20. The method of  claim 16 , wherein the one or more peptides contains at least one amino acid selected from the group consisting of D-amino acids, unnatural amino acids, non-proteinogenic amino acids, N-methyl alanine, alpha-amino butyric acid, and alpha-amino isobutyric acid. 
     
     
       21. The method of  claim 16 , wherein the inflammation is inflammation of the skin or musculoskeletal inflammation. 
     
     
       22. The method of  claim 16 , wherein the one or more peptides is selected from the group consisting of peptides comprising the sequence LWAEAK (SEQ ID NO:008) and peptides comprising the sequence LVAEAK (SEQ ID NO:030). 
     
     
       23. A method of restoring a youthful phenotype in skin in a patient in need thereof, comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a peptide of  claim 1  in an amount sufficient to restore a youthful phenotype in skin.